The nature of the system controlling sodium excretion in man and other terrestrial mammals has been investigated for many years. Until the early 1960's, sodium excretion in mammals was believed to be controlled by changes in one of two factors: 1) glomerular filtration rate ("GFR"); and 2) mineralocorticoid hormone activity. In 1961, however, it was demonstrated by DeWardener et al., Clinical Science, Vol. 21, pp. 249-258 (1961), that an additional factor, or factors, regulated sodium excretion. It was observed that increased sodium excretion (hereinafter referred to as "natriuresis") occurred in response to extracellular fluid volume expansion in dogs despite constant GFR and mineralocorticoid hormone activity.
Since the observations of DeWardener et al., considerable effort has been employed by researchers in the field to isolate and identify other factors involved in the regulation of sodium excretion. In the belief that there exists a principal modulator of sodium excretion, a number of researchers have pursued a substance referred to as the "natriuretic hormone." See, e.g., Bricker, N. S., "The Control of Sodium Excretion With Normal and Reduced Nephron Populations: Pre-Eminence of Third Factor,"Am. J. Med., 43:313 (1967); see also Haber and Haupert, Hypertension, 4:315 (1987).
Prior to the present invention, natriuretic factors acting on the Na/K/ATPase pump had not been isolated in pure form, chemically defined, or synthesized in the laboratory. In fact, there is evidence that more than one biochemical compound may be responsible for observed effects. The inhibitors of active sodium transport inhibiting fractions studied by most investigators is a small molecule with a molecular weight of less than 500 Daltons (as indicated by ultra filtration). Some groups have reported that the compound could be a peptide, but recent studies have not supported the petide nature of the factor.
Considerable research over the last several decades has focused on adverse effects of a high sodium diet (for example in hypertension) and on the renal retention of sodium in a number of diseases, including heart disease, liver failure and pre-menstrual syndromes. Diuretic agents are widely used today in an effort to prevent or reverse these pathologic states. However, most potent widely used diuretics not only increase sodium excretion but may also lead to undesirable loss of potassium. Unfortunately, the potassium supplements prescribed for replacement are generally unpalatable, expensive and difficult for patients to tolerate on a continuing basis.
There thus exists a need for a potent natriuretic compound which specifically augments sodium excretion but does not produce the loss of potassium. The present invention satisfies this need and provides related advantages as well.